Bibliographic updates

Claude MOLINA* & Jacques GAYRAUD**

1. Recombinant Allergens (RA) in Paediatrics
2. Biomarkers of Omalizumab’s (O) potential efficacy in severe allergic asthma
3. Omalizumab in the treatment of Chronic Urticaria
4. Role of Th17 and IL17 in Allergo-Immunology
5. Infections and asthma

1. Recombinant Allergens (RA) in Paediatrics

Theme: Allergens
Key words: Recombinant allergens – Major allergens

The identification of allergenic components with the techniques of molecular biology and selective IgE reactivity to allergens (major or minor) represent significant breakthroughs towards the personalised diagnosis and treatment for allergic patients (R.Coudert et J.Just  Bulletin de l’Acad. Nle Médecine  Mars 2013 sous presse).

In this way, it is possible to make out several molecular families and to characterize the main epitopes as follows:
1) Thermoresistant LTPs (Lipid Transfer Protein), present in raw or cooked fruit and vegetables (eg. Ara h 9) and responsible for sometimes severe respiratory and food allergies, mostly observed in Southern Europe.
2) Thermolabile PR-10s (Pathogenesis Related proteins), responsible for oral syndrome and cross-allergy (eg. apple-birch).
3) Profilines: minor allergens, in pollens and plants, often without clinical consequences.
4) Tropomyosin: a muscular protein, frequent in invertebrates (shrimp, dust mites, eg. Der P 10), responsible for cross-allergy between dust mites, shell-fish, and snails).

Identifying the specific major allergen in children may help to avoid sometimes hazardous provocative testing; this is the case for peanuts, where simple sensitivity to rArah 2 confirms the diagnosis.

As for prognosis, the association between Der p1 and Der p2 predicts a good efficacy of dust-mite immunotherapy (inversely not recommended if sensitivity to Pen a 1, the shrimp tropomyosin, is also associated).

Several attempts at immunotherapy with RAs have been successfully performed (Birch, Timothy, Cat) but the high heterogeneity of molecular profiles (S.Tripodi JACI 2013 129 3 834-839) and changes in pre-clinical IgE response over time (L.Hatzler  JACI 2013 130 4 894-901), make ‘customised’ allergenic preparation and its validity quite risky.

2. Biomarkers of Omalizumab (O) potential efficacy in severe allergic asthma

Theme: Severe Asthma - Treatment
Key words: Omalizumab – FE NO – Severe allergic asthma – Blood eosinophilia - Periostin

In severe allergic,  primarily Th2-weighted asthma (A), American and European specialists recommend the use of one of 3 dosages of  O (75, 150 or 300 mg), in a single 4-weekly injection. In France, only the 75 and 150 mg doses are authorised. In order to avoid useless and costly treatments, the role of biomarkers (BMs) likely to predict O’s efficacy is analysed in the following paper (N.A.Hanania et al AJRCCM 7 March 2013 on line).

850 patients, aged 12-75 and suffering from severe allergic asthma were enrolled (427 asthmatics and 423 placebo), in an American multicentre randomised study. 3 BM were used at the beginning of the treatment: FeNO for 397 patients (46.4%), blood eosinophilia for 797 (93.8%) and Periostin (P) for 534 (62.8%). The objective was to assess reduction in A exacerbations during treatment (48 weeks, on age- and weight- adjusted US established doses), BMs were divided in 2 subgroups: low and high level.

Compared to placebo, the 3 high level BMs revealed O’s clear efficiency in the reduction in A exacerbations.
Comparing the two subgroups statistically showed high level BM superiority over low:
- for FeNO : 53% vs 16% (P : 0.001)
- for blood eosinophilia : 32% vs 9% (P : 0.05)
- for P dosage : 30% vs 3% (P : 0.07)

True, there was no significant difference between the 2 subgroups at the end of treatment as to the patients’ quality of life and A symptomatology, with the 3 BMs expressing airway inflammation.

But, if one looks at the action mode of monoclonal antibodies, FeNO would be the best marker for O assessment (anti-IL4 and anti-IL5), whereas P, the marker for eosinophilia and IL13 action, would be more sensitive to Lebrikizumab.

It should be noted (with N.C Thomson et al JACI 2013 1008-1016) that all inflammatory biomarkers are clearly reduced in current smokers with severe asthma.

3. Omalizumab (O) in the treatment of Chronic Urticaria

Theme: Skin allergology
Key words: Omalizumab – Chronic urticaria

Two papers deal with this theme: a Canadian one (C.H.Song Ann. Allergy Asthma, Immunol. 2013 113-117), an open trial on 16 patients, and an American one (M.Maurer et al NEJM  2013  368  924-935), a randomised multicentre trial on 323 patients.

All the authors agree on the definition, i.e. eruption of hives and itching for over 6 weeks uncontrollable by antihistamines. O efficacy was assessed using 7-day activity scores and itch-severity scores.

- In the Canadian trial, O (not reimbursed by the State for this indication) was administered every 2 to 4 weeks at 150mg doses. A remission was obtained with 10 patients, 6 after the 1st injection, 2 after the 3rd and 2 after the 6th. Failure or cessation of O in 2 cases. In the long term : 3 were asymptomatic 1 year after the last dose, 1 after 9 months; 7 continued treatment every 4 to 8 weeks; 3 had stopped completely. On the whole, a mixed result.

- In the American trial, 323 patients aged 12-75 (average 42), 85% white, 41% suffering from Angioedema; High level of IgE (average 78 UI),), received 3 subcutaneous injections every 4 weeks at age-, height- and weight-adjusted doses (82 at 75mg, 83 at 150mg, 79 à 300mg and 79 placebo) ; they were monitored for 16 weeks, with daily and weekly electronic itch-severity scores (0 to 21, average 14 in the 4 groups).

Primary end-point: After 12 weeks, decrease in itch-severity score by at least 5 points, and in hives number and size; Statistics revealed a significant decrease for the 150 and 300mg groups (P = or ≥0.001).

Secondary end-point: proportions of remission (free of hives and itching) In post-hoc analyses, the results are : 10% for placebo, 18% for the 75mg group, 23% for the 150mg and 53% for the 300mg group; therefore, clinical improvement depending on the dosage in both analyses; however a maximum of side effects at 300mg.

That is to say that O’s place remains to be defined in the treatment of Chronic Urticaria.

4. Role of Th17 and IL17 in Allergo-Immunology

Theme: Immunology
Key words: Th17 lymphocytes – IL17A and IL 17C interleukins – auto-immunity – CD24 – Allergic alveolitis – Respiratory infection

As a lymphocyte subpopulation, newly identified in the CD4+ Th framework, Th17 cells seem to play an important role in the mechanism of allergic and auto-immune (AI) diseases. Moreover, they are co-responsible for the release of Interleukins 17, a family of 6 components from IL17A to IL17F, with 17A and 17C the most important.

1) TH17 and AI: Increased incidence of AI is due to the joint action of genetic and environmental factor. A remarkable US-German paper (M. Kleinewierfiled et al  Nature  on line  March 2013) showed, in cell culture and on a murine experimental  Encephalomyelitis (an animal model for Multiple Sclerosis MS,), the pivotal role of Th17cells. Indeed, high salt-concentration in mice, whether metabolic or food-induced, worsens Encephalitis since nervous tissues are invaded by TH17s which release pro-inflammatory cytokines: IL147A, GM-CSF, IL2 TNFα. The paper’s authors carefully avoid extrapolating to humans the relationship between hyper salted diets (Western fast-food) and occurrence of AIs such as MS and Psoriasis, but suggest clinical trials of food salt reduction in individuals at risk for developing AI disease.

2) IL17A and hypersensitivity pneumonitis (HP): In a murine model of HP provoked by Saccharopolyspora rectivirgula, cause of Farmer’s Lung disease, still frequent in Canada, the authors (S.A Hasan et Al JACI 2013 on line) show that IL17A is crucial for the development of lung fibrosis, which is significantly attenuated by depletion of neutrophils . Moreover Monocytes/Macrophages and Neutrophils (and not Lymphocytes) are the main cells-type that expressed IL17A in experimental HP.

3) IL17C and lung infection: (P.Pfeiffer et al AJRCell Molecul.Dec 2012) IL17C enhances  inflammatory response of the lung epithelium of mice infected with Pseudomonas aeruginosa, an innate immune response, suppressed by cigarette smoke, one of the mechanisms explaining the harmful effects of smoking.

5. Infections and asthma

Theme: Asthma - Infection
Key words: Infections – Asthma – Microbiome – Vitamin D

As recalled in an excellent review by T.T.Hansel et al (The Lancet 2013 381 March 9 861-871), the respiratory tract is literally ‘bombarded’ by bacteria and viruses (in addition to dusts and allergens). It adapts its response with Dendritic, Epithelial and Lymphocyte cells. It is well-known that one healthy adult harbours an estimated 100 trillions of bacteria which can today be identified through genomic methods (16 S ribosomal subunit sequence): The microbiome is mainly located in the colon but also present in the respiratory system.

In asthmatics, the mucosal immune response is variable. The authors categorise it according to the ‘7 ages of asthma’ (A) with its consequences on practical points of view:
1) Already in the foetus, although maternal exposure to bacteria and farm dusts has a protective effect against-asthma,  vitamin D deficiency in the mother may cause ‘wheezing’ in the new-born (NB) that some paediatricians hesitate to label as asthma, 
2) At birth, the NB already carries approximately one hundred bacteria in the colon and the umbilical cord contains an increased concentration of Th2 chemokines. In a recent Danish study in 662 subjects, the authors  found  a colonisation of neonates airways by Moraxella Catarhhalis and Hemophilus Influenzae, (N.V Folsgaard et al AJRCCM 2013 6 589-595) which is associated with inflammatory immune response and may result in chronic inflammation
3) During infancy (up to 18 months), SRV (Syncitial Respiratory Virus) is the major cause of bronchiolitis, leading often to future A.
4) During early childhood (up to 5 years), virus and allergens account for the classical atopic march towards asthma.
5) During later childhood and adolescence (6 to 16), children are vulnerable to viruses responsible for persistence of A, but also to Mycoplasma Pneumoniae and Chlamydia Pneumoniae which justify the use of macrolides.
6) In adults, the respiratory microbiome is abundant and diversified, but it is RHV (Respiratory Human Virus) which is the major cause of A exacerbations.
7) Finally, in elderly subjects, the range of concomitant diseases causes a loss of lung function and vulnerability to bacterial and viral infections, justifying recommendation of influenza vaccination in this age group. The authors conclude that these advances in the role of microbes in asthma may allow personalised treatment in the near future

Comments and questions welcome:

*Pr. Claude Molina
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**Dr Jacques Gayraud
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Last updated 25 July 2014